PROJECT SUMMARY/ABSTRACT This application is a competing revision of our parent NIA grant AG056850 entitled ?The Role of Inflammation and NGF Dysfunction in the Evolution of Alzheimer Disease Pathology in Down syndrome?. Down syndrome (DS) is an outstanding natural genetic model for the study of neuropathological mechanisms of Alzheimers disease (AD) and for identifying potential AD biomarkers. The study of the Alzheimer's preclinical phase is crucial for the development of new future treatments that could eventually slow down or stop the progression of the disease before any cognitive decline. The overall goal of our multisite parent R01 is to investigate novel biomarkers at the earliest preclinical stages of AD in DS integrating data from post-mortem brain studies (Aim 1), primary human cell cultures studies (Aim 2), and biological fluids (plasma and CSF) studies in a large well-characterized cohort of DS subjects (Aim 3). This Competing revision will evaluate additional biochemical biomarkers of neurodegeneration and oxidative stress as well as neuroimaging biomarkers in our well-characterized cohort coupled with in vitro studies in normal and DS human cortical cultures designed to provide insight into the molecular mechanisms underlying the biomarker profiles observed in the clinical cohort. The specific hypothesis driving this competing revision is that basal forebrain (BF) atrophy is an early marker of neurodegeneration that will antedate hippocampal and cortical atrophy and will trigger A? deposition, NGF dysfunction and oxidative stress. To test this hypothesis, we will accomplish three Specific aims. Aim1: To study BF atrophy in relation to both A? deposition and plasma and CSF AD biomarkers, including NGF dysfunction biomarkers developed in the funded R01 and additional biochemical biomarkers of neurodegeneration and oxidative stress. Aim2: To perform additional mechanistic studies in normal and DS primary human cortical cultures. Aim3: To integrate BF degeneration and NGF dysfunction into a global model of AD pathogenesis. Together with the original R01 aims, these additional experiments are designed to generate an unprecedented profile of the time course of appearance and interaction of AD-related neurodegenerative changes in DS. As such, this competing revision will provide additional critical information creating synergies with the original proposal and maximizing the information to be obtained from the clinical cohort, biological fluid samples and in vitro studies.! !